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WO2023016525A1 - Composé en tant qu'inhibiteur de la kinase atr - Google Patents

Composé en tant qu'inhibiteur de la kinase atr Download PDF

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Publication number
WO2023016525A1
WO2023016525A1 PCT/CN2022/111868 CN2022111868W WO2023016525A1 WO 2023016525 A1 WO2023016525 A1 WO 2023016525A1 CN 2022111868 W CN2022111868 W CN 2022111868W WO 2023016525 A1 WO2023016525 A1 WO 2023016525A1
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Prior art keywords
tert
phenyl
pyrazin
butyl
isoxazol
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PCT/CN2022/111868
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English (en)
Chinese (zh)
Inventor
彭程
张绍云
张楠
钱梦飞
李中洋
宋国伟
邹罡
袁海卿
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Suzhou Ark Biopharmaceutical Co Ltd
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Suzhou Ark Biopharmaceutical Co Ltd
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Priority claimed from CN202110930540.XA external-priority patent/CN115703768B/zh
Application filed by Suzhou Ark Biopharmaceutical Co Ltd filed Critical Suzhou Ark Biopharmaceutical Co Ltd
Priority to US18/681,269 priority Critical patent/US20250026742A1/en
Priority to CN202280054394.1A priority patent/CN117794924A/zh
Publication of WO2023016525A1 publication Critical patent/WO2023016525A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the disclosure belongs to the field of medicinal chemistry, and in particular relates to an ATR kinase inhibitor and its preparation method and application.
  • ATR is an ATM Rad3-related protein kinase
  • ATM Ataxia-telangiectasia mutated, telangiectasia ataxia mutation
  • DNA-PKcs DNA-dependent protein kinase catalytic subunit, DNA-dependent protein kinase Catalytic subunit
  • PI3KKs Phosphoinositide 3 kinase-related protein kinases, phosphoinositide 3 kinase-related protein kinases
  • DNA damage Affected by external pressure or the internal environment of the body, cells undergo DNA damage, especially DNA single-strand or double-strand breaks (Double Strand Breaks, DSB) and replication stress.
  • DNA damage Response DNA-damage response, DDR
  • DDR DNA-damage response
  • ATM and ATR are activated by DNA damage and DNA replication stress, but their DNA damage specificity and function are different.
  • ATM is mainly activated by double-strand DNA breaks, while ATR responds to a wide range of DNA damage, including DSBs and various DNA lesions that interfere with replication. The two act synergistically to signal DNA damage and regulate downstream processes.
  • many types of cancer cells are defective in some of their DNA repair processes, such as ATM signaling, thereby displaying a greater dependence on their remaining intact DNA repair proteins, such as ATR.
  • ATR DNA repair proteins
  • Synthetic lethality refers to the occurrence of single gene inactivation that is tolerated for cell survival in a pair of genes that are functionally similar or compensatory, whereas simultaneous disruption of multiple genes results in cell death.
  • the treatment strategy based on synthetic lethality has three advantages: first, ATM is one of the most common abnormal genes in cancer, according to the COSMIC database, it is in tumors and hematological malignancies 167 distinct ATM somatic mutations (excluding variants of unknown origin) were observed, thus therapeutic strategies based on synthetic lethality can combat most cancer mutations; second, corresponding patients can be easily identified based on the high selectivity of genetic mutations ; Finally, combined with chemotherapy drugs can improve its efficacy and reduce the dose, avoid or reduce adverse reactions.
  • ATR kinase inhibitors in preclinical and clinical research stages include Berzosertib (VX-970), Ceralaserti (AZD6738), Elimusertib (BAY-1895344), ART0380, RP-3500, VX-803 and M1774 disclosed in WO2010071837A1.
  • VX-970 is undergoing Phase I/II or Phase II clinical trials for indications such as prostate cancer, small cell lung cancer, ovarian cancer, urothelial cancer and non-small cell lung cancer.
  • the clinical treatment of AZD6738 for breast cancer, head and neck squamous cell carcinoma, gastric cancer and non-small cell lung cancer has entered phase II.
  • ART0380 for the treatment of ovarian cancer RP-3500 for the treatment of solid tumors, and VX-803 for the treatment of breast cancer are currently in phase I/II clinical trials.
  • BAY-1895344 is in the treatment of lymphoma and solid tumors, and M1774 in the treatment of solid tumors is in phase I clinical trials.
  • ATR kinase inhibitors may be effective either as single agents or as sensitizers to radiotherapy or genotoxic chemotherapy.
  • Ring A, ring B and ring C are 6 to 10 membered aryl or 5 to 10 membered heteroaryl;
  • R 2 and R 5 are selected from hydrogen, deuterium, halogen, C 1-6 alkyl, amino and C 1-6 alkoxy;
  • each R 3 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl and is selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl substituted by the substituent of the group;
  • R 4 is selected from hydrogen, deuterium, C 1-6 alkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, C 1-6 alkylamino and (C 1-3 alkyl) 2 amino;
  • each R 6 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkoxy, C 1-6 alkyl and is selected from cyano, amino, hydroxyl, halogen, C 1-6 C 1-6 alkyl substituted by substituents of 6 alkyl and C 1-6 alkoxy;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-6 alkyl, cyano, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, C 1-6 alkoxy, C 1-6 6 alkylamino and C 1-6 alkyl, 3 to 7 membered cycloalkane substituted by a substituent selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy and 3 to 7 membered heterocyclyl; and
  • n1, n2 and n3 is any integer of 0 to 2.
  • aminopyrazine compounds provided by the present disclosure have high inhibitory activity on ATR, excellent drug efficacy, in vitro/in vivo pharmacokinetic properties and safety, and have high clinical application prospects.
  • Figure 3 The change (percentage) of mouse tumor volume after administration of different administration groups
  • One aspect of the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof:
  • Ring A, ring B and ring C are 6 to 10 membered aryl or 5 to 10 membered heteroaryl;
  • R 2 and R 5 are selected from hydrogen, deuterium, halogen, C 1-6 alkyl, amino and C 1-6 alkoxy;
  • each R 3 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl and is selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl substituted by the substituent of the group;
  • R 4 is selected from hydrogen, deuterium, C 1-6 alkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, C 1-6 alkylamino and (C 1-3 alkyl) 2 amino;
  • each R 6 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkoxy, C 1-6 alkyl and is selected from cyano, amino, hydroxyl, halogen, C 1-6 C 1-6 alkyl substituted by substituents of 6 alkyl and C 1-6 alkoxy;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-6 alkyl, cyano, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, C 1-6 alkoxy, C 1-6 6 alkylamino and C 1-6 alkyl, 3 to 7 membered cycloalkane substituted by a substituent selected from cyano, amino, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy and 3 to 7 membered heterocyclyl; and
  • n1, n2 and n3 is any integer of 0 to 2.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein n1 is 0 or 1; n2 is 1 or 2, and n3 is preferably 0 or 1.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein n1 is 0 or 1; n2 is 0 or 1; and n3 is 0 or 1.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein the ring A and ring B are selected from From phenyl and 5 to 6-membered heteroaryl; preferably, the ring A and ring B are selected from phenyl and 6-membered heteroaryl; more preferably, the ring A and ring B are selected from phenyl and pyridine Most preferably, said ring A and ring B are selected from phenyl groups.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein the ring C is 5 to 6 Member heteroaryl;
  • the ring C is a 5-member heteroaryl; More preferably, the ring C is selected from isoxazole, oxadiazole and thiadiazole; Most preferably, the ring C is selected from From isoxazole and oxadiazole.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof is formula Ia
  • the indicated compound or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q 1 , Q 2 , n1, n2 and n3 are as defined in formula I.
  • the compound represented by formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof is a compound represented by formula I-b or Its pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope labels:
  • Ring C is a 5-membered heteroaryl group
  • L is CR 10a R 11a or NR 14a ;
  • n4a is 0, 1 or 2;
  • R 9a is selected from oxygen and NR 7 ;
  • R 10a and R 11a are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino; or R 10 and R 11 are together with the atoms to which they are attached Forming a 3 to 7 membered cycloalkyl group or comprising 1 or 2 3 to 7 membered heterocyclic groups selected from oxygen, nitrogen and sulfur;
  • R 14a is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocyclic group, the replacement is selected Substituted by substituents from halogen, hydroxyl, amino, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino;
  • R 1 , R 2 , R 3 , R 6 , R 7 , Q 1 , n1, n2 and n3 are as defined in formula I.
  • the compound represented by formula I or formula I-b or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof is formula I-b-1
  • Ring C, R 1 , R 2 , R 3 , R 6 , R 7 , Q 1 , n1, n2, n3, L, n4a, R 9a and R 12a are as defined in formula Ib.
  • the compound shown in formula I, formula I-b, formula I-b-1 or formula I-b-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or Isotope markers wherein the ring C is 5 to 6-membered heteroaryl; preferably, the ring C is 5-membered heteroaryl; more preferably, the ring C is selected from isoxazole, oxadiazole and Thiadiazole; most preferably, the ring C is selected from isoxazole and oxadiazole.
  • the compound shown in formula I-b, formula I-b-1 or formula I-b-2 or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein n4a is 0 or 1; preferably, n4a is 0.
  • the compound represented by Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein R 9a is selected from oxygen and NH; preferably, R 9a is selected from oxygen.
  • the compound represented by Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein L is CR 10a R 11a , R 10a and R 11a are each independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 alkoxy; preferably, L is CR 10a R 11a , R 10a and R 11a are each independently selected from hydrogen and C 1-6 alkyl; more preferably, L is CR 10a R 11a , both R 10a and R 11a are C 1-6 alkyl; most preferably, L is CR 10a R 11a , R 10a and R 11a are all methyl groups.
  • the compound represented by Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein R 10a and R 11a together with the atoms they are connected to form a 3 to 7 membered cycloalkyl group or contain 1 or 2 3 to 7 membered heterocyclic groups selected from oxygen, nitrogen and sulfur; the 3 to 7 membered Cycloalkyl is cyclopropanyl.
  • the compound represented by Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein R 12a and R 13a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; preferably, R 12a and R 13a are each independently selected from hydrogen, Deuterium, halogen, hydroxyl and C 1-6 alkyl; more preferably, R 12a and R 13a are each independently selected from hydrogen, deuterium, methyl, fluorine and hydroxyl; further preferably, R 12a and R 13a are each independently is selected from hydrogen and fluorine; most preferably R 12a is hydrogen and R 13a is fluorine.
  • the compound represented by Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label wherein R 14a is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, hydroxyethyl and
  • the compound represented by formula Ib or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof wherein for R 10a , R 11a , R 12a and R 13a are as defined in formula Ib; preferably, for R 10a , R 11a and R 12a are as defined in formula Ib; more preferably, for Most preferably, for
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, Prodrugs or isotope labels wherein R 2 and R 5 are each independently selected from hydrogen, deuterium, halogen and C 1-6 alkyl; preferably, R 2 and R 5 are each independently hydrogen or deuterium.
  • the 6-membered heterocyclic group is any one of the following structures:
  • R 8 is selected from hydrogen, deuterium, C 1-6 alkyl and 3 to 7 membered cycloalkyl; preferably, R 8 is hydrogen.
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, Prodrugs or isotope labels wherein R 3 is halogen or halogen-substituted C 1-6 alkyl, preferably F or CF 3 .
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, Prodrugs or isotope labels wherein R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and halogen substituted C 1-6 alkyl; preferably, R 3 is selected from hydrogen atom, halogen and halogen substituted C 1-6 alkyl; more preferably, R 3 is selected from hydrogen atom, F and CF 3 .
  • the compound represented by formula I or formula Ia or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein R is selected from C 1-6 alkyl, 3 to 7 membered cycloalkyl, C 1-6 alkylamino and (C 1-3 alkyl) 2 amino; preferably, R is methyl or any of the following structures:
  • the compound represented by Formula I or Formula Ia or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof wherein R 4 and R 5 Together with the atoms they are connected to form a 5 to 7 membered heterocyclic group comprising 1 to 3 selected from oxygen, nitrogen and sulfur, the 5 to 7 membered heterocyclic group is preferably any of the following structures:
  • n4 is an integer selected from 0 to 2;
  • R9 is selected from oxygen and NR7 ;
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino; or R 10 and R 11 are together with the atoms to which they are attached Forming a 3 to 7 membered cycloalkyl group or comprising 1 or 2 3 to 7 membered heterocyclic groups selected from oxygen, nitrogen and sulfur;
  • R 14 is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocyclic group, the replacement is selected Substituted by substituents from halogen, hydroxyl, amino, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino;
  • R 7 is as defined in formula I.
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula Ib-1 or Formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, Prodrugs or isotopic labels wherein each R 6 is independently selected from hydrogen, deuterium and fluorine.
  • Q 1 is selected from C 1-6 alkylene, -CO-,
  • each R 7 is independently selected from hydrogen, deuterium, methyl and cyano; preferably, each R 7 is independently selected from hydrogen and methyl.
  • n4 is 0 or 1 in the formula II-a or II-b.
  • R 9 in the formula II-a, II-b or II-c is selected from oxygen and NH.
  • R 10 and R 11 in the formula II-a are each independently selected from hydrogen, deuterium, C 1-6 alkyl and C 1-6 alkoxy; preferably, R 10 and R 11 are each independently selected from hydrogen and C 1-6 alkyl; more preferably, R 10 and R 11 are each independently selected from hydrogen and methyl.
  • R 10 and R 11 form a 3 to 7 membered cycloalkyl group together with the atoms they are connected to or contain 1 or 2 3 selected from oxygen, nitrogen and sulfur to 7-membered heterocyclic group; the 3- to 7-membered cycloalkyl group is cyclopropanyl.
  • R 12 and R 13 in the formula II-a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; preferably , R 12 and R 13 are each independently selected from hydrogen, deuterium, halogen, hydroxyl and C 1-6 alkyl; more preferably, R 12 and R 13 are each independently selected from hydrogen, deuterium, methyl, fluorine and hydroxyl ; Further preferably, R 12 and R 13 are each independently selected from hydrogen and fluorine; most preferably, R 12 is hydrogen, and R 13 is fluorine.
  • R in the formula II-b is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, hydroxyethyl and
  • Typical compounds of the present disclosure include, but are not limited to:
  • the present disclosure also provides a preparation method of a compound represented by formula I,
  • step S1 is reacted in the presence of bistrifluoroacetyliodobenzene.
  • step S2 is reacted in the presence of bis-pinacol borate.
  • step S2 is reacted in the presence of a base.
  • the base in step S2 is selected from inorganic bases and organic bases.
  • the inorganic base described in step S2 is selected from one or more of sodium hydride, potassium phosphate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide Various.
  • the organic base described in step S2 is selected from triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate , sodium tert-butoxide, potassium tert-butoxide and 1,8-diazabicycloundec-7-ene.
  • step S2 is reacted in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • step S3 is reacted in the presence of a base.
  • the base in step S3 is selected from inorganic bases and organic bases.
  • the inorganic base described in step S3 is selected from one or more of sodium hydride, potassium phosphate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide Various.
  • the organic base described in step S3 is selected from triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate , sodium tert-butoxide, potassium tert-butoxide and 1,8-diazabicycloundec-7-ene.
  • step S3 is reacted in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • step S4 is reacted in the presence of an acid.
  • the acid in step S4 is selected from one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid.
  • the method when there is an amino group in the R group in the compound of formula a, b, c, d, I, the method further includes the steps of protecting and deprotecting the amino group.
  • the protecting group is selected from Boc and Cbz.
  • step S1 is reacted in the presence of hydrazine hydrate.
  • step S2 is reacted in the presence of a base.
  • the base in step S2 is selected from inorganic bases and organic bases.
  • the inorganic base described in step S2 is selected from one or more of sodium hydride, potassium phosphate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide Various.
  • the organic base described in step S2 is selected from triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate , sodium tert-butoxide, potassium tert-butoxide and 1,8-diazabicycloundec-7-ene.
  • step S2 occurs in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate reaction.
  • step S3 is reacted in the presence of a base.
  • the base in step S3 is selected from inorganic bases and organic bases.
  • the inorganic base described in step S3 is selected from one or more of sodium hydride, potassium phosphate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide Various.
  • the organic base in step S3 is selected from triethylamine, pyridine, diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, tert-butanol One or more of sodium, potassium tert-butoxide and 1,8-diazabicyclounde-7-ene.
  • step S3 is reacted in the presence of dibromotriphenylphosphine.
  • step S4 is reacted in the presence of a base.
  • the base in step S4 is selected from inorganic bases and organic bases.
  • the inorganic base described in step S4 is selected from one or more of sodium hydride, potassium phosphate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide Various.
  • the organic base described in step S4 is selected from triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate , sodium tert-butoxide, potassium tert-butoxide and 1,8-diazabicycloundec-7-ene.
  • step S4 is reacted in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the method when there is an amino group in the R group in the compound of formulas c, d, and I, the method further includes the steps of protecting and deprotecting the amino group.
  • the protecting group is selected from Boc and Cbz.
  • the present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compounds shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B of the present disclosure.
  • the unit dosage of the pharmaceutical composition described in the present disclosure is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01%-99.99% of Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A of the present disclosure. Or a compound shown in Table B or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the compounds shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B of the present disclosure Or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label.
  • the pharmaceutical composition contains 0.5%-99.5% of the compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B of the present disclosure Or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label.
  • the pharmaceutical composition contains 1%-99% of the compounds shown in Formula I, Formula I-a, Formula I-b or Table A or Table B of the present disclosure or pharmaceutically acceptable salts and esters thereof , isomers, solvates, prodrugs or isotopic labels.
  • the pharmaceutical composition contains 2%-98% of the compounds shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B of the present disclosure Or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label.
  • the pharmaceutical composition of the present disclosure contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 1%-99% of pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical compositions of the present disclosure contain 2%-98% of pharmaceutically acceptable carriers, diluents or excipients.
  • Compounds shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B involved in the present disclosure or their pharmaceutically acceptable salts, esters, isomers, solvates , prodrugs, or isotope labels, and mixtures and compositions containing them, can be administered into living organisms via any route of administration.
  • the route of administration can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal cavity inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.
  • Compounds shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B involved in the present disclosure or their pharmaceutically acceptable salts, esters, isomers, solvates , prodrugs or isotope markers and mixtures and compositions containing them can be formulated into a single dose, which contains the active compound of the present invention as well as carriers, excipients, etc., and the dosage form can be tablets, capsules, injections , granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches and lotions, etc.
  • dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostats, isotonic regulators and antibacterial agents. Adhesive, etc.
  • Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press 2005 Published in 2010, so those skilled in the art can easily prepare.
  • the dosage of the compound of the present disclosure can be 0.01 to 500 mg/kg per day , the preferred daily dose is 1-100 mg/kg, which can be administered in single or multiple doses.
  • the present disclosure also provides a compound shown in Formula I, Formula Ia, Formula Ib, Formula Ib-1, Formula Ib-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, Solvates, prodrugs or isotope labels or pharmaceutical compositions comprising them, wherein the isotope is selected from 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P , 35 S, 18 F and 36 Cl, preferably, the isotope is 2 H.
  • the present disclosure also provides a compound represented by formula I, formula Ib, formula Ib-1 or formula Ib-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label Or or a pharmaceutical composition comprising it, wherein ring C is replaced by an isotope selected from 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S , 18 F and 36 Cl, preferably, the isotope is 2 H.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, Application of solvate, prodrug or isotope label or pharmaceutical composition containing it in the preparation of medicine for inhibiting ATR kinase.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, Use of solvates, prodrugs or isotope labels or pharmaceutical compositions containing them in the preparation of medicines for preventing and/or treating diseases or disorders mediated by ATR kinase.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, Use of solvates, prodrugs or isotopic labels or pharmaceutical compositions comprising them in the manufacture of medicaments for the prevention and/or treatment of diseases or disorders mediated by ATR kinase; wherein said diseases or disorders are excessive or abnormal Diseases, disorders and conditions of cell proliferation; preferably, the diseases, disorders and conditions are selected from cancer and myeloproliferative disorders; more preferably, the cancer is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer , prostate cancer, colorectal cancer, lung cancer, bone cancer, brain cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, squamous cell carcinoma, Glioma, Meningiom
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, A solvate, prodrug or isotopic label or a pharmaceutical composition comprising the same for use as a medicament.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, A solvate, prodrug or isotopic label, or a pharmaceutical composition comprising the same, for use as an ATR kinase inhibitor.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, A solvate, a prodrug or an isotope label or a pharmaceutical composition comprising the same for use in the prevention and/or treatment of ATR kinase mediated diseases or conditions.
  • the present disclosure also provides a compound shown in Formula I, Formula I-a, Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, Solvates, prodrugs or isotopic labels or pharmaceutical compositions comprising them for the prevention and/or treatment of diseases or disorders mediated by ATR kinase; wherein said diseases or disorders are diseases of excessive or abnormal cell proliferation, Disorders and conditions; preferably, the diseases, disorders and conditions are selected from cancer and myeloproliferative disorders; more preferably, the cancer is selected from the group consisting of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, tumor Rectal cancer, lung cancer, bone cancer, brain cancer, esophagus cancer, tongue cancer, stomach cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, squamous cell carcinoma, glioma, meninges Hodgkin's Ly
  • the present disclosure also provides a method for inhibiting ATR kinase, which comprises administering a therapeutically effective amount of the formula I, formula I-a, formula I-b, formula I-b-1, formula I-b-2, or shown in Table A or Table B to a patient in need.
  • the present disclosure also provides a method for preventing and/or treating ATR kinase-mediated diseases or conditions, which comprises administering a therapeutically effective amount of formula I, formula I-a, formula I-b, formula I-b-1, formula I-b- 2 or a compound shown in Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label or a pharmaceutical composition comprising the same.
  • the present disclosure also provides a method for preventing and/or treating ATR kinase-mediated diseases or conditions, which comprises administering a therapeutically effective amount of formula I, formula I-a, formula I-b, formula I-b-1, formula I-b- 2 or a compound shown in Table A or Table B or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label or a pharmaceutical composition comprising it; wherein the disease or disease are diseases, disorders and conditions of excessive or abnormal cell proliferation; preferably, said diseases, disorders and conditions are selected from cancer and myeloproliferative disorders; more preferably, said cancers are selected from skin cancer, bladder cancer, ovarian cancer, Breast cancer, stomach cancer, prostate cancer, colorectal cancer, lung cancer, bone cancer, brain cancer, esophagus cancer, tongue cancer, stomach cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, squamous cell carcinoma Cystoid cell carcinoma
  • the present disclosure further provides a method for treating diseases mediated by ATR kinase, the mammal may be a human, or may be a non-human mammal, for therapeutic purposes, comprising administering formula I, formula I-a, formula I-a, Compounds shown in Formula I-b, Formula I-b-1, Formula I-b-2 or Table A or Table B or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope labels or compounds comprising them pharmaceutical composition.
  • C 1-6 alkyl alone or in combination means a saturated linear or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -Pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3 ,-Dimethyl-2-butyl and so on.
  • C 1-6 alkyl is any one of methyl, ethyl, isopropyl and tert-butyl.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • C 1-6 alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. group, which is an alkylene group containing 1 to 6 carbon atoms.
  • alkylene examples include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • Alkylene groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment.
  • 3 to 7 membered cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means a saturated cycloalkyl group having 3 to 7, especially 3 to 6 carbon atoms, including Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • Particular "C 3-7 cycloalkyl” is cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • C 1-6 alkylamino denotes an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C 1-6 alkyl
  • C 1-6 alk Base means as defined above, correspondingly, "C 1-6 alkylamino” includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl Base-2-pentylamin
  • C 1-6 alkoxy alone or in combination, denotes the group C 1-6 alkyl-O-, wherein “C 1-6 alkyl” denotes as defined above.
  • heterocyclic group refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur.
  • This cyclic group can be
  • the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized.
  • the hydrogen atoms on the "heterocyclyl” are independently optionally substituted with one or more substituents described herein.
  • Heterocyclyl can be attached to the parent molecule through any ring atom in the ring.
  • 3- to 7-membered heterocyclyl refers to a monocyclic heterocyclyl containing 3 to 7 carbon atoms and heteroatoms; for example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl , tetrahydrofuryl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
  • 3 to 7-membered cycloalkylamino means the amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is replaced by at least one C 3-7 cycloalkyl group, "C 3- 7 cycloalkyl” means as defined above.
  • 3 to 7-membered heterocyclylamino means, alone or in combination, an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one 3 to 7-membered heterocyclic group, "3 to 7 "Heterocyclyl” means as defined above.
  • aryl means any stable 6- to 10-membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl or biphenyl and the like.
  • heteroaryl means an aromatic ring group formed by replacing a carbon atom on the ring with at least one heteroatom selected from sulfur, oxygen or nitrogen.
  • This aromatic ring group can be a 5-7 membered monocyclic ring or a 7-12 bicyclic group.
  • the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, such as thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl , naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuryl, quinolinyl, isoquinolyl, quinazolinyl, etc.
  • arylC 1-6 alkyl means that a C 1-6 alkyl group is substituted by one or more aryl groups, aryl and C 1-6 alkyl being as defined above.
  • heteroarylC 1-6 alkyl means that a C 1-6 alkyl group is substituted by one or more heteroaryl groups, heteroaryl and C 1-6 alkyl are as defined above.
  • amino alone or in combination denotes a primary (-NH 2 ), secondary (-NH-) or tertiary amino group
  • halogen alone or in combination denotes fluorine, chlorine, bromine or iodine. Especially fluorine, chlorine or bromine.
  • cyano alone or in combination refers to the group -CN.
  • hydroxy alone or in combination refers to the group -OH.
  • substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • replacement means that a certain group is completely replaced by another group, for example, a methylene group is replaced by a heteroatom such as an oxygen atom or a nitrogen atom, and the like.
  • the bond configuration is not specified, i.e. the key can be or both Two configurations.
  • key represents a single configuration, for In the chemical structures of the compounds described in this disclosure, the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • isotope label means that an isotope can be introduced into any compound involved in the present invention, and the introduced isotope can be 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, preferably, the introduced isotope can be 2 H, 3 H, 13 C, 14 C, more preferably, the introduced isotope is 2 H, specific isotopic derivatives can be obtained by conventional technical preparation.
  • pharmaceutically acceptable salt means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts.
  • Pharmaceutically acceptable salts are described in pharmaceutically salts by SM Berge in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977).
  • the pharmaceutically acceptable non-toxic acid addition salt means the salt formed by the compound in the present invention and organic or inorganic acid
  • organic or inorganic acid includes but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydrogen iodide acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, P-toluenesulfonic acid and malic acid, etc.
  • Non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; organic base salts, such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
  • alkali metal salts such as lithium, sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic base salts such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
  • Oxalyl chloride oxalyl chloride
  • PBS Phosphate Buffered Saline
  • the chromatographic column is filled with silica gel.
  • the silica gel 300-400 mesh
  • the preparative chromatographic plate is produced by Yantai Jiangyou Silica Gel Development Co., Ltd.
  • the chromatographic column used by ISCO is produced by Changzhou Santai Technology Co., Ltd.
  • the LC-MS liquid mass spectrometry chromatograph uses ACQUITY Arc from Waters Company equipped with QDa Detector. A Waters XBridge C18 chromatographic column (specification 2.1 ⁇ 50 mm, 3.5 ⁇ m) was used. Mass Spectrometry (MS) using an ESI source indicates only the molecular weight M of the parent molecule, usually reported as [M+H] + .
  • the injection volume was determined by the sample concentration; the flow rate was: 1.2 mL/min; the HPLC peaks were recorded and read by UV-Vis wavelengths at 220 nm and 254 nm.
  • the mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). Gradient elution conditions are shown in Table C and Table D below:
  • the NMR spectrum is obtained using a Varian 400MHz nuclear magnetic resonance spectrometer, usually using CDCl 3 and DMSO-d 6 as solvents, and reporting chemical shifts in ppm.
  • the various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 1c (0.6 g).
  • the aqueous phase was concentrated into a solid, and ethyl acetate (50 mL) and methanol (30 mL) were added to the solid, stirred for 0.5 hours and filtered, and the filtrate was concentrated to obtain a black oil (4-(propyl-2-sulfinimide) Phenyl)boronic acid 2a (1.3 g), was crude and was used directly in the next step without further purification.
  • tert-Butyl-5-formyl-1H-benzo[d][1,2,3]triazole-1-carbamate 3d (0.14g, 0.566mmol), hydroxylamine hydrochloride (0.048g , 0.68mmol) was prepared according to the method similar to the first step of Example 1 to obtain yellow oil tert-butyl (E)-5-((hydroxyimine) methylene)-1H-benzo[d][1, 2,3] Triazole-1-carboxylate 3e (75 mg).
  • the tert-butyl (tert-butoxycarbonyl) (3-(3-(4-cyano-2 fluorophenyl) isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl ) pyrazin-2-yl) carbamate 4c (100mg, 0.177mmol), nickel chloride hexahydrate (127mg, 0.532mmol) and sodium borohydride (20mg, 0.532mmol) according to the fourth step similar to Example 1
  • the method prepares light yellow oil tert-butyl (3-(3-(4-(aminomethyl)-2-fluorophenyl)isoxazol-5-yl)-5-(4-(isopropyl Sulfonyl)phenyl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 4d (28 mg).
  • tert-butyl(tert-butoxycarbonyl)(5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-(((phenoxycarbonyl)amino)methylene)benzene yl)isoxazol-5-yl)pyrazin-2-yl)carbamate 5a (15mg, 0.02mmol), triethylamine (3 ⁇ L) and methyl hydrochloride (15mg, 0.2mmol)
  • the method of the second step of Example 5 prepares white solid tert-butyl (tert-butoxycarbonyl) (3-(3-(4-((3-methylureido) methylene) phenyl) isoxazole- 5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 7a (11 mg).
  • reaction solution was stirred at 55° C. for two hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-acetylene yl-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 11a (433 mg).
  • tert-butyl tert-butoxycarbonyl
  • reaction solution was stirred at 90° C. for two hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(4-(N,S-dimethylsulfonimido)phenyl)pyrazin-2-yl)carbamate Ester 12c (145 mg).
  • phenyl) pyrazin-2-yl) carbamate 12c (145mg, 0.23mmol) in methanol (2mL) solution, add nickel chloride hexahydrate (164mg, 0.69mmol) and sodium borohydride successively at room temperature (26 mg, 0.69 mmol). After the reaction solution was stirred at room temperature for 1 hour, it was quenched with saturated aqueous ammonium chloride (2 mL).
  • reaction solution was stirred at 90° C. for two hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(4-(N-methylpropyl-2-ylsulfonimide)phenyl)pyrazin-2-yl) Carbamate 13d (180 mg).
  • tert-butyl (tert-butoxycarbonyl) 3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(4-(N-methylpropyl-2-yls
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (5-(4 -(isopropylsulfonyl)phenyl)-3-(3-(4-nitrophenyl)isoxazol-5-yl)-pyrazin-2-yl)carbamate 14c (0.17g) .
  • tert-butyl (tert-butoxycarbonyl) 5-(4 -(isopropylsulfonyl)phenyl)-3-(3-(4-nitrophenyl)isoxazol-5-
  • tert-butyl (3-(3-(4-aminophenyl)isoxazol-5-yl)-5- (4-(Isopropylsulfonyl)phenyl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 14d (100 mg).
  • tert-butyl (tert-butoxycarbonyl) (5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-((phenoxycarbonyl)amino)phenyl)isoxazole- 5-yl)pyrazin-2-yl)carbamate 14e (20mg, 0.026mmol) in acetonitrile (3mL) was added methylamine hydrochloride (4mg, 0.052mmol), and the mixture was stirred at 50°C for 2 hours .
  • Tert-butyl (tert-butoxycarbonyl) (5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-((phenoxycarbonyl)amino)phenyl)isoxazole- 5-yl)pyrazin-2-yl)carbamate 14e (20mg, 0.026mmol) was dissolved in ammonia methanol solution (7M, 3mL) and the mixture was stirred at 50°C for 2 hours.
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (5-(4 -(isopropylsulfonyl)phenyl)-3-(3-(5-nitropyridin-2-yl)isoxazol-5-yl)pyrazin-2-yl)carbamate 19c (0.12 g).
  • tert-butyl (tert-butoxycarbonyl) (5-(4 -(isopropylsulfonyl)phenyl)-3-(3-(5-nitropyridin-2-yl)is
  • reaction solution was stirred at room temperature for 16 hours, it was diluted with ethyl acetate (40 mL), the mixture was filtered through celite, washed with aqueous sodium bicarbonate (40 mL) until neutral, and then poured into a separatory funnel.
  • tert-butyl (3-(3-(5-aminopyridin-2-yl)isoxazol-5-yl) -5-(4-(Isopropylsulfonyl)phenyl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 19d (75 mg).
  • tert-butyl (tert-butoxycarbonyl) (5-bromo-3-(3-(2-fluoro-4-nitrophenyl) isoxazol-5-yl) pyrazin-2-yl ) Carbamate 20b (0.30g, 0.52mmol) in a mixed solution of 1,4-dioxane (15mL) and water (1.5mL), at room temperature ( ⁇ 20°C) followed by 4-isopropylsulfonyl Phenylboronic acid (0.12 g, 0.52 mmol), potassium carbonate (0.22 g, 1.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.076 g, 0.01 mmol).
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(2-fluoro-4-nitrophenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 20c( 0.13g).
  • reaction solution was stirred at room temperature for 16 hours, it was diluted with ethyl acetate (40 mL), the mixture was filtered through celite, washed with aqueous sodium bicarbonate (40 mL) until neutral, and then poured into a separatory funnel.
  • tert-butyl (tert-butoxycarbonyl) (3-(3-(4-amino-2-fluorophenyl)iso Oxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 20d (85 mg).
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (5-(4 -(isopropylsulfonyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoxazol-5-yl )pyrazin-2-yl)carbamate 21c (0.06g).
  • tert-butyl (tert-butoxycarbonyl) (5-(4 -(isopropylsulfonyl)phenyl)
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoxazol-5-yl)-5-(4-(propan-2-ylsulfinyl )phenyl)pyrazin-2-yl)carbamate 22a (0.07g).
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-Cyanophenyl)isoxazol-5-yl)-5-(4-(cyclopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 23b (0.13 g).
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyano-3-fluorophenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 24c( 0.11g).
  • Oxyzin-2-yl) (tert-butoxycarbonyl) carbamate 24d (26 mg, 0.046 mmol) in acetonitrile (3 mL) was added successively with 1H-pyrazole-1-carboxamidine hydrochloride (7 mg, 0.046 mmol) and N,N-Diisopropylethylamine (9 ⁇ L). Stir at room temperature ( ⁇ 20°C) for 16 hours.
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(4-(dimethylcarbamoyl)phenyl)pyrazin-2-yl)carbamate 25a (0.16g) .
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain 4-(5-(3-((tert-butoxycarbonyl )amino)-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)isoxazol-3-yl)methyl benzoate 26c (0.33 g).
  • reaction system was quenched by adding excess saturated sodium sulfite aqueous solution (40mL), the organic phase was separated, the aqueous phase was extracted three times with dichloromethane (30mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and Column chromatography gave 5-bromobenzo[b]thiophene 1,1-dioxide 27a (0.97 g) as a white solid.
  • reaction solution was stirred at 95° C. for three hours. After cooling to room temperature, ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution. The mixed solution was filtered with diatomaceous earth, the resulting solution was separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the combined organic phase was concentrated and separated by column chromatography to obtain tert-butyl (tert-butoxycarbonyl) (3-(3 -(4-cyanophenyl)isoxazol-5-yl)-5-(1,1-dioxy-2,3-dihydrobenzothiophen-5-yl)pyrazin-2-yl) Carbamate 27d (0.25 g).
  • tert-Butyl(5-bromo-3-ethynyl-pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (0.5 g, 1.26 mmol) and (E)-4-(bromomethyl) Benzaldehyde oxime 28a (0.40g, 1.88mmol) was prepared according to a method similar to the second step of Example 1 to obtain tert-butyl (5-bromo-3-(3-(4-bromomethylphenyl)isoxazole- 5-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 28b (350 mg).
  • tert-butyl (3-(3-(4-acetamidinomethylphenyl) isoxazol-5-yl)-5-bromopyrazin-2-yl) (tert-butoxycarbonyl) carbamate 28c (60mg, 0.10mmol) and 4-isopropylsulfonylphenylboronic acid (35.1mg, 0.15mmol) were prepared according to a method similar to the third step of Example 1 to obtain tert-butyl (3-(3-(4-ethyl Amidinomethylphenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 28d( 8mg).
  • tert-Butyl(5-bromo-3-ethynyl-pyrazin-2-yl)(tert-butoxycarbonyl)carbamate 500 mg, 1.26 mmol
  • (E)-4-iodobenzaldehyde oxime 29a 463.6mg, 1.88mmol
  • tert-butyl 5-bromo-3-(3-(4-iodophenyl)isoxazol-5-yl)pyrazine- 2-yl)(tert-butoxycarbonyl)carbamate 29b (400 mg).
  • tert-butyl (5-bromo-3-(3-(4-iodophenyl) isoxazol-5-yl) pyrazin-2-yl) (tert-butoxycarbonyl) carbamate 29b (400.0mg, 0.62mmol) and 4-isopropylsulfonylphenylboronic acid (169.6mg, 0.74mmol) were prepared according to a method similar to the third step of Example 1 to obtain tert-butyl (tert-butoxycarbonyl) (3- (3-(4-Iodophenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)carbamate 29c (90 mg).

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Abstract

L'invention concerne un inhibiteur de la kinase ATR tel que représenté dans la formule I, son procédé de préparation et son utilisation.
PCT/CN2022/111868 2021-08-13 2022-08-11 Composé en tant qu'inhibiteur de la kinase atr Ceased WO2023016525A1 (fr)

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Citations (9)

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CN102300862A (zh) * 2008-12-19 2011-12-28 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
WO2013049719A1 (fr) * 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase atr
WO2013049720A1 (fr) * 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase atr
WO2013071085A1 (fr) * 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Composés de pyrazine utiles comme inhibiteurs de kinase atr
WO2014062604A1 (fr) * 2012-10-16 2014-04-24 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de la kinase atr
CN103958507A (zh) * 2011-09-30 2014-07-30 沃泰克斯药物股份有限公司 可用作atr激酶抑制剂的化合物
CN103987709A (zh) * 2011-09-30 2014-08-13 沃泰克斯药物股份有限公司 用于制备可用作atr激酶抑制剂的化合物的方法
WO2018029117A1 (fr) * 2016-08-10 2018-02-15 Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer
WO2022063869A2 (fr) * 2020-09-24 2022-03-31 Merck Patent Gmbh Composés pour le traitement d'infections virales

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102300862A (zh) * 2008-12-19 2011-12-28 沃泰克斯药物股份有限公司 用作atr激酶抑制剂的化合物
WO2013049719A1 (fr) * 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase atr
WO2013049720A1 (fr) * 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de kinase atr
CN103958507A (zh) * 2011-09-30 2014-07-30 沃泰克斯药物股份有限公司 可用作atr激酶抑制剂的化合物
CN103987709A (zh) * 2011-09-30 2014-08-13 沃泰克斯药物股份有限公司 用于制备可用作atr激酶抑制剂的化合物的方法
WO2013071085A1 (fr) * 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Composés de pyrazine utiles comme inhibiteurs de kinase atr
WO2014062604A1 (fr) * 2012-10-16 2014-04-24 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs de la kinase atr
WO2018029117A1 (fr) * 2016-08-10 2018-02-15 Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Nouveaux inhibiteurs d'atr destinés à être utilisés dans le traitement du cancer
WO2022063869A2 (fr) * 2020-09-24 2022-03-31 Merck Patent Gmbh Composés pour le traitement d'infections virales

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Title
KNEGTEL RONALD, CHARRIER JEAN-DAMIEN, DURRANT STEVEN, DAVIS CHRIS, O’DONNELL MICHAEL, STORCK PIERRE, MACCORMICK SOMHAIRLE, KAY DAV: "Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 11, 13 June 2019 (2019-06-13), US , pages 5547 - 5561, XP093034718, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00426 *

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